Pharmaceutical dosage forms are known which provide a variety of drug release profiles, including immediate release, sustained release, and delayed release. That is, it may be desirable, for a particular drug, to prevent drug release after drug administration until a certain amount of time has passed (so-called "timed release"), to provide substantially continuous release over a predetermined time period (so-called "sustained release") or to provide release immediately following drug administration (i.e., "immediate release"). For some types of drugs, it is preferred to release the drug in "pulses," wherein a single dosage form provides for an initial dose of drug followed by a release-free interval, after which a second dose of drug is released, followed by one or more additional release-free intervals and drug release "pulses." Pulsatile drug delivery is useful, for example, with active agents that have short half-lives and must be administered two or three times daily, with active agents that are extensively metabolized presystemically, and with active agents which lose the desired therapeutic effect when constant blood levels are maintained. These types of agents have pharmacokinetic-pharmacodynamic relationships that are best described by a clockwise "hysteresis loop." A drug dosage form that provides a pulsatile drug release profile is also useful for minimizing the abuse potential of certain types of drugs, i.e., drugs for which tolerance, addiction and deliberate overdose can be problematic.
Because a precise and effective pulsatile drug delivery system is difficult to formulate and manufacture, there are few such dosage forms that have been commercialized. There are, however, several patents and literature references pertaining to pulsatile drug delivery. See, for example, U.S. Pat. No. 5,413,777 to Sheth et al., directed to a pulsatile once-a-day delivery system for the administration of minocycline; U.S. Pat. No. 5,260,068 to Chen, directed to a multiparticulate pulsatile drug delivery system; U.S. Pat. No. 4,777,049 to Magruder et al., directed to an osmotic delivery system for constant release of a drug with intermittent release "pulses"; U.S. Pat. No. 5,391,381 to Wong et al., directed to a drug dispenser for delivering individual drug-containing units in a "pulsatile" manner; PCT Publication No. WO 98/32424, pertaining to pulsatile delivery of diltiazem hydrochloride; U.S. Pat. Nos. 5,472,708 and 5,260,069 to Chen; Ishino et al. (1992) "Design and Preparation of Pulsatile Release Tablet as a New Oral Drug Delivery System," Chem. Pharm. Bull. 40(11):3036-3041; Cohen et al. (1994), "Pulsatile Release from Microencapsulated Liposomes," J. Liposome Res. 349-360; and Gazzaniga et al. (1994), "Chronotopic Drug Delivery Systems for Pulsatile and/or Site-Specific Release," 21.sup.st. Proc. Int. Symp. Controlled Release Bioact. Mater., pp. 744-745.
The present invention is directed in part to a novel pulsatile drug delivery system which is straightforward to manufacture and provides precisely timed drug release "pulses" at desired intervals.
Methylphenidate hydrochloride (HCl), the hydrochloride salt of .alpha.-phenyl-2-piperidine-acetic acid methyl ester (available commercially as Ritalin.RTM.), is a central nervous system stimulant that is used in the treatment of Attention Deficit Disorder ("ADD"), a commonly diagnosed nervous system illness in children that is characterized by both distractability and impulsivity. Methylphenidate HCl is also used to treat a related disorder, Attention Deficit Hyperactivity Disorder ("ADHD"), in which symptoms of hyperactivity are present along with the symptoms of ADD. The drug is additionally used in the symptomatic treatment of narcolepsy, depression, and the cognitive decline associated with Acquired Immunodeficiency Syndrome ("AIDS") or AIDS-related conditions, as well as for mood elevation, particularly in terminally ill patients with diseases such as cancer. Methylphenidate exists as four distinct isomers, as follows: ##STR1##
The drug as used in therapy is a racemic mixture of the d- and l-threo enantiomers, which have been acknowledged as more active than the erythro pair.
Because of its potential for tolerance (loss of clinical efficacy when constant blood levels are maintained), short-half life and potential for abuse, methylphenidate is a primary candidate for use in conjunction with the drug delivery systems of the invention.
It has recently been found that the d-threo enantiomer of methylphenidate, rather than the l-threo enantiomer, is primarily responsible for the therapeutic effectiveness of methylphenidate, particularly in ADHD. See Srinivas et al. (1992), "Enantioselective Pharmacokinetics and Pharmacodynamics of d,l-threo-Methylphenidate in Children with Attention Deficit Hyperactivity Disorder," Clin. Pharmacol. Ther. 52:561-568, who compared the results of administering dl-threo, d-threo, and l-threo methylphenidate to children suffering from ADHD, and determined that the pharmacodynamic activity of methylphenidate resides in the d-threo isomer. Ding et al. (1997), "Chiral Drugs: Comparison of the Pharmacokinetics of [.sup.11 C]d-threo and l-threo-Methylphenidate in the Human and Baboon Brain," Psychopharmacology 131:71-78, and Eckerman et al. (1991), "Enantioselective Behavioral Effects of threo Methylphenidate in Rats," Pharmacology Biochemistry & Behavior 40:875-880, also studied the relative therapeutic efficacy of the d-threo and l-threo isomers, concluding that d-threo-methylphenidate was responsible for the therapeutic efficacy of the racemate.
It has also been suggested that l-threo methylphenidate not only makes no contribution to therapeutic efficacy, but in fact contributes to undesirable side effects associated with administration of racemic methylphenidate, e.g., insomnia, euphoria, development of tolerance to the drug, and potential for abuse. Accordingly, several researchers have proposed administering methylphenidate as the pure d-threo isomer rather than as the racemic mixture of d-threo and l-threo isomers. See, e.g., U.S. Pat. No. 5,908,850 to Zeitlin et al., U.S. Pat. No. 5,874,090 to Baker et al., and U.S. Pat. No. 5,922,736 to Dariani et al. Also see U.S. Pat. No. 5,837,284 to Mehta et al., which describes a pulsatile drug delivery system for administration of d-threo methylphenidate.
A drawback of the prior art, however, is that the disclosed dosage forms are ineffective for individuals who do not respond, or respond inadequately, to methylphenidate therapy or to a second central nervous system ("CNS") stimulant (e.g., an analeptic agent such as d-amphetamine, as found in the commercial ADHD product Adderol.RTM.). It has now been discovered that co-administering methylphenidate, and particularly d-threo methylphenidate, with a second CNS stimulant, particularly an analeptic agent such as d-amphetamine, gives rise to a therapeutically effective pharmaceutical formulation useful in treating individuals who do not respond, or respond inadequately, to methylphenidate therapy or to the second CNS stimulant, when administered as individual active agents. It has also been found that the aforementioned combination of active agents can provide an increased therapeutic benefit to patients who do respond to methylphenidate therapy or to the second CNS stimulant, e.g., to an analeptic agent such as d-amphetamine.
Accordingly, the present invention provides novel pharmaceutical dosage forms for the administration of d-threo methylphenidate along with at least one additional active agent comprising a second CNS stimulant. The novel dosage forms provide for pulsatile drug release, thereby maximizing efficacy (i.e., the loss of clinical efficacy over time), reducing the potential for abuse or noncompliance. The dosage forms also provide for therapeutic efficacy in individuals who do not respond, or respond inadequately, to methylphenidate or to the second CNS stimulant when these agents are administered alone, and provide enhanced therapeutic efficacy in individuals who are responsive to methylphenidate and other CNS stimulants such as d-amphetamine. No art of which applicants are aware describes drug delivery systems as now provided herein.
To the best of applicants' knowledge, the pharmaceutical dosage forms of the invention are previously unknown and completely unsuggested by the art.